Project Summary: Like all synapses during normal activity, endbulb synapses formed by auditory nerve fibers onto cochlear nucleus bushy cells show use-dependent changes in synaptic strength. At normal auditory nerve firing rates, endbulb synapses show considerable depression, which can have a major impact on the bushy cell's behavioral role of relaying and improving the timing of auditory nerve spikes for sound localization; however, the kinetics of these changes are not well understood under physiological conditions. The specific aims of this project are to determine the dynamics of use-dependent changes in synaptic strength, as well as the mechanisms underlying them. This work will be carried out using patch-clamp recordings of bushy cells in mouse brain slices. The mechanisms of depression will be considered first, by testing the contributions of presynaptic vesicle depletion and postsynaptic receptor desensitization and saturation. In addition, an unusual form of depression at the endbulb will be examined, which has been proposed to involve reduced presynaptic calcium influx, but has never been directly tested. It will also be determined how depression is mitigated by both recovery processes and facilitation, and how these processes depend on presynaptic calcium levels. In addition, high levels of activity at this synapse can lead to significant delayed release. Current clamp studies will test whether delayed release disrupts the precisely timed responses of bushy cells. The contribution of presynaptic calcium levels to delayed release will also be examined. Taken together, these studies will provide important information about the mechanisms by which timing information is transformed by auditory nerve synapses during realistic activity. Relevance: This work may help to improve the efficiency of cochlear implants, by identifying patterns of auditory nerve stimulation that will be effective, or ineffective, when processed by the cochlear nucleus. This work will also provide information for implants that stimulate the brain directly, for patients who lack a functioning auditory nerve. [unreadable] [unreadable]